title: Intercalating, cytotoxic, antitumour activity of 8-chloro and 4-morpholinopyrimido [4',5':4,5]thieno(2,3-b)quinolines.
abstract: Circular dichroism, hydrodynamic methods, absorbance and fluorescence titration's were employed to study the interaction of 8-chloropyrimido[4',5':4,5]thieno(2,3-b)quinolin-4(3H)-one (chloro-PTQ) and 4-morpholinopyrimido[4',5':4,5]thieno(2,3-b)quinoline (morpholino-PTQ) with DNA. The association constant of chloro-PTQ and morpholino-PTQ were of the order of 10(5) and 10(6) M(-1). The fluorescence properties at ionic strength of 10mM are best fit by the neighbor exclusion model, with Ki of 0.3 x 10(4) M(-1) to 3.2 x 10(6) M(-1). CD spectra indicate that stacking of these compounds with DNA induces strong helicity in the usually disordered structure of the double strand. Viscosity experiments with sonicated rod like DNA fragments, produced a calculated length of 2.4A/bound of chloro/morpholino-PTQ molecule. The binding of chloro/morpholino-PTQ to DNA increased the melting temperature by about 1.5-7.0 degrees C. The cytotoxicity of these compounds on K-562, HL-60, Colo-205 and B16F10 melanoma are quite similar and IC(50) was in the range of 1.1-8muM. The anticancer efficacy against B16F10 melanoma has provided evidence of major anticancer activity for morpholino-PTQ. Single or multiple i.p. doses of compounds showed high level of activity against the subcutaneous (s.c.) grafted B16 melanoma with a significant increase in life span (161% and 272%). The aim of this study was to analyze the physicochemical properties of the chloro/morpholino-PTQ in an attempt to understand their superior biological activity. This research offers a new intercalation functional group to DNA targeted drug design.
authors.affiliation: Department of Studies and Research in Biochemistry, Kuvempu University, Shivagangotri, Davanagere-577 002, India; Department of Biochemistry, Indian Institute of Science, Bangalore-560012, India.
authors.forename: M S
authors.initials: MS
authors.lastname: Shahabuddin
authors.forename: M
authors.initials: M
authors.lastname: Gopal
authors.forename: Sathees C
authors.initials: SC
authors.lastname: Raghavan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000633:toxicity*; D002417:Cattle; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D017606:Chlorine Compounds / Q000737:chemistry* / Q000633:toxicity; D002942:Circular Dichroism; D004247:DNA / Q000737:chemistry; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D009025:Morpholines / Q000737:chemistry; D009368:Neoplasm Transplantation; D011743:Pyrimidines / Q000737:chemistry*; D011804:Quinolines / Q000737:chemistry* / Q000633:toxicity*; D013053:Spectrophotometry; D013438:Sulfhydryl Compounds / Q000737:chemistry*; D017186:Titrimetry; D014783:Viscosity
chemical_list: D000970:Antineoplastic Agents; D017606:Chlorine Compounds; D009025:Morpholines; D011743:Pyrimidines; D011804:Quinolines; D013438:Sulfhydryl Compounds; C037574:morpholine; D004247:DNA; C427203:calf thymus DNA